Discovery of novel 2,4-diarylaminopyrimidine hydrazone derivatives as potent anti-thyroid cancer agents capable of inhibiting FAK

J Enzyme Inhib Med Chem. 2024 Dec;39(1):2423875. doi: 10.1080/14756366.2024.2423875. Epub 2024 Nov 19.

Abstract

In this work, thirty 2,4-diarylaminopyrimidine-based hydrazones were designed, synthesised, and their anti-thyroid cancer activity were explored. The majority of compounds exhibit moderate to excellent cytotoxic activity against FAK overexpressing TPC-1 cells, with IC50 values ranging from 0.113 to 1.460 μM. Among them, compound 14f displayed exceptional anti-proliferative effect against TPC-1 cells (IC50 = 0.113 μM) and potent FAK inhibitory potency (IC50 = 35 nM). In silico studies indicated that compound 14f could well bind to FAK (Focal Adhesion Kinase) and have favourable pharmacokinetic profiles. In addition, compound 14f could inhibit the phosphorylation of FAK at Tyr397, Tyr576/577 and Tyr925, and did not affect the expression level of FAK in TPC-1 cells. Compound 14f was also effective in inhibiting the proliferation and migration of thyroid cancer cells TPC-1. Thus, these novel 4-arylaminopyrimidine hydrazone derivatives exhibited potent anti-thyroid cancer activities through the inhibition of FAK.

Keywords: 2,4-Diarylaminopyrimidine; Antiproliferative activities; FAK; Hydrazone; Thyroid cancer.

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation* / drug effects
  • Dose-Response Relationship, Drug*
  • Drug Discovery
  • Drug Screening Assays, Antitumor*
  • Focal Adhesion Kinase 1* / antagonists & inhibitors
  • Focal Adhesion Kinase 1* / metabolism
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Humans
  • Hydrazones* / chemical synthesis
  • Hydrazones* / chemistry
  • Hydrazones* / pharmacology
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Pyrimidines* / chemical synthesis
  • Pyrimidines* / chemistry
  • Pyrimidines* / pharmacology
  • Structure-Activity Relationship
  • Thyroid Neoplasms* / drug therapy
  • Thyroid Neoplasms* / pathology

Substances

  • Hydrazones
  • Antineoplastic Agents
  • Pyrimidines
  • Protein Kinase Inhibitors
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • Focal Adhesion Protein-Tyrosine Kinases

Grants and funding

This work was supported by the National Natural Science Foundation of China [No. U2004123 and 82273782], the National Natural Science Foundation of Henan [No. 242300421472] and the Training Program for Young Key Teachers of Colleges and Universities in Henan Province [2023GGJS008].